8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1.
8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1.
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DOI：
10.1016/j.freeradbiomed.2013.04.011
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发表时间：
2013-08
影响因子：
7.4
通讯作者：
Boldogh, Istvan
中科院分区：
文献类型：
--
作者：
Hajas, Gyorgy;Bacsi, Attila;Aguilera-Aguirre, Leopoldo;Hegde, Muralidhar L.;Tapas, K. Hazra;Sur, Sanjiv;Radak, Zsolt;Ba, Xueqing;Boldogh, Istvan
8-氧-7,8-二氢鸟嘌呤（8-oxoG）是活性氧（ROS）诱导的最丰富的DNA碱基损伤之一。8-oxoG在哺乳动物基因组中的积累被认为是氧化应激的标志，与炎症有因果关系，并被认为与衰老过程和各种衰老相关疾病有关。出乎意料的是，缺乏8-氧鸟嘌呤DNA糖基化酶-1 （OGG1）活性并在其基因组中积累8-氧鸟嘌呤的小鼠具有正常的表型和寿命；事实上，它们对炎症和氧化应激的抵抗力都有所增强。在DNA碱基切除修复（BER）过程中，OGG1切除并产生游离的8-oxoG碱基。在本研究中，我们报道了在8-oxoG碱基存在的情况下，OGG1与鸟嘌呤核苷酸无和gdp结合的Rac1蛋白发生物理相互作用。这种相互作用导致GDP→GTP的快速交换，而不是GTP→GDP的体外交换。重要的是，细胞内8-oxoG碱基水平的升高增加了gtp结合的Rac1的比例。反过来，Rac1-GTP通过核膜相关的NADPH氧化酶4型介导ROS水平的增加。这些结果显示了OGG1与8-oxoG复合物与氧化还原信号和细胞反应相关的新机制。
8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant DNA base lesions induced by reactive oxygen species (ROS). Accumulation of 8-oxoG in the mammalian genome is considered a marker of oxidative stress, to be causally linked to inflammation, and is thought to contribute to aging processes and various aging-related diseases. Unexpectedly, mice that lack 8-oxoguanine DNA glycosylase-1 (OGG1) activity and accumulate 8-oxoG in their genome have a normal phenotype and longevity; in fact, they show increased resistance to both inflammation and oxidative stress. OGG1 excises and generates free 8-oxoG base during DNA base-excision repair (BER) processes. In the present study, we report that in the presence of the 8-oxoG base, OGG1 physically interacts with guanine nucleotide-free and GDP-bound Rac1 protein. This interaction results in rapid GDP→GTP, but not GTP→GDP, exchange in vitro. Importantly, a rise in the intracellular 8-oxoG base levels increases the proportion of GTP-bound Rac1. In turn Rac1-GTP mediates an increase in ROS levels via nuclear membrane-associated NADPH oxidase type 4. These results show a novel mechanism by which OGG1 in complex with 8-oxoG is linked to redox signaling and cellular responses.
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影响因子：
7.4
作者：
Hajas, Gyorgy;Bacsi, Attila;Aguilerra-Aguirre, Leopoldo;German, Peter;Radak, Zsolt;Sur, Sanjiv;Hazra, Tapas K.;Boldogh, Istvan
通讯作者：
Boldogh, Istvan
影响因子：
5.3
作者：
Bacsi, Attila;Chodaczek, Grzegorz;Boldogh, Istvan
通讯作者：
Boldogh, Istvan
影响因子：
4.6
作者：
Das, Gokul C.;Bacsi, Attila;Boldogh, Istvan
通讯作者：
Boldogh, Istvan
影响因子：
4.1
作者：
Fleming, IN;Gray, A;Downes, CP
通讯作者：
Downes, CP
影响因子：
14.9
作者：
Dizdaroglu, M;Jaruga, P;Rodriguez, H
通讯作者：
Rodriguez, H